1. Field of the Invention
The present invention relates to a series of dihydro-imidazole (also referred to herein as imidazoline) compounds. More specifically, the present invention relates to a novel series of 4,5-diphenyl-2-amino-4,5-dihydro-imidazole derivatives having certain geometric configuration. This invention also relates to methods of making these compounds. The compounds of this invention are P2X7 ion channel blockers and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases having an inflammatory component, including inflammatory bowel disease, rheumatoid arthritis and disease conditions associated with the central nervous system, such as stroke, Alzheimer's disease, etc.
2. Description of the Art
The P2X7 receptor, a ligand-gated ion channel, is present on a variety of cell types, mostly the ones believed to be involved in the inflammatory/immune process. In particular, macrophages, mast cells and lymphocytes (T and B) are known to have P2X7 receptor sites. Activation of the P2X7 receptor by extracellular nucleotides, particularly, adenosine triphosphate, leads to the release of interleukin-1β (IL-1β) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes.
Thus, compounds exhibiting antagonistic activity at the P2X7 receptor site are expected to show anti-inflammatory activity and thereby exhibit therapeutic efficacy in diseases due to P2X7 receptor activation. The diseases that are implicated include rheumatoid arthritis, Alzheimer's disease, stroke and inflammatory bowel disease, psoriasis and various other diseases where an inflammatory component is present. It has also been reported that macrophages are also involved in the thermal injuries such as burns (see, e.g., Schwacha, Burns Vol. 29 pages 1-14 (2003)).
As noted above, the P2X7 protein is mainly localized to immune system cells such as macrophages and microglia, see for example, Collo et al., Neuropharmacology Vol. 36 pages 1277-1283 (1997). Also as noted above, activation of P2X7 results in the release of proinflammatory substances such as IL-1β and IL-18, see for example, Hlide et al., Journal of Neurochemistry Vol. 75 pages 965-972 (2000); Perregaux et al., Journal of Immunology Vol. 165 pages 4615-4623 (2000). This is further demonstrated by the fact that the mice lacking the P2X7 receptor are unable to release IL-1β via ATP stimulation. See Solle et al., Journal of Biological Chemistry Vol. 276 pages 125-132 (2001).
It has been reported that certain compounds act as P2X7 antagonists. For example, WO99/29660 and WO99/29661 disclose that certain adamantane derivatives exhibit P2X7 antagonistic activity having therapeutic efficacy in the treatment of rheumatoid arthritis and psoriasis. Similarly, WO99/29686 discloses that certain heterocyclic derivatives are P2X7 receptor antagonists and are useful as immunosuppressive agents and treating rheumatoid arthritis, asthma, septic shock and atherosclerosis. Finally, WO00/71529 discloses certain substituted phenyl compounds exhibiting immunosuppressing activity. All of the references described herein are incorporated herein by reference in their entirety.
It is an object of this invention to provide a novel series of compounds, which can modify the activity of P2X7 receptor and thus the release of the mediators of inflammation. It is further an object of this invention to provide a series of compounds that can treat or alleviate symptoms of inflammation caused due to the activation of P2X7 receptor. A still further object of this invention is to provide pharmaceutical compositions that are effective in the treatment or prevention of a variety of disease states, including the diseases associated with the central nervous system, such as stroke and Alzheimer's disease, inflammatory bowel disease, rheumatoid arthritis, and other diseases where an inflammatory component is present.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description to follow.